Pharmacogenomics of Microtubule-targeting Agents

The project

Microtubule targeting agents including taxanes and epothilones are clinically effective cytotoxic chemotherapy for treating various solid tumors, but are often limited by serious toxicity that result in dose reductions/delays or even discontinuation of therapy. Sensory peripheral neuropathy is a major dose-limiting toxicity that manifests as nerve damage, initially experienced as numbness/tingling and burning sensations in hands and feet. Severe microtubule targeting agent-induced sensory peripheral neuropathy symptoms cause significant impairment of daily activities such as writing, dressing, or even walking. The Kroetz lab seeks to understand how genetic variation influences a patient’s risk of developing sensory peripheral neuropathy during chemotherapy.

The main goal of our pharmacogenomics approach is to uncover clinically relevant genetic associations to identify sensory peripheral neuropathy risk and define the pathophysiological mechanisms behind such risk. A previous genome-wide association study conducted in our lab has recently identified several common genetic variants involved within genetic pathways of axon outgrowth and nerve regeneration associated with paclitaxel-induced sensory peripheral neuropathy. The studies here will extend these findings and test the central hypothesis that both common and rare variants contribute to interindividual variability in microtubule targeting agent-induced toxicity.

Replication of genetic findings remains a challenge in translating pharmacogenomic studies into clinical outcomes. We have isolated ~1700 potential samples for replication in the BioVU repository linked with electronic health records at the Vanderbilt University. DNA samples will be genotyped on the Illumina Multi-Ethnic Genotyping Array. Novel genetic variants and candidate genes previously identified from Aim 1 and earlier genome-wide association studies will be analyzed.

Functional genomic studies will aim to screen for the most biologically relevant genes. Our in vitro studies are motivated to understand the effects of the identified genes and genetic variants on neuronal function during chemotherapy exposure. These genetic effects will be characterized by measuring global changes in neurite extension, neurite complexity and cellular signaling. Functional validation of genetic predictors will explain how this toxicity develops, identify who is susceptible to developing chemotherapy-induced sensory peripheral neuropathy, and inform innovative therapeutic strategies to prevent or treat this toxicity.